Pyrimidine derivative, and preparation method therefor and use thereof

Abstract

Provided is a pyrimidine derivative, a preparation method and a use thereof, wherein the pyrimidine derivative is selected from a compound represented by Formula (I), or a tautomer, an enantiomer, a diastereomer, a mesomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof. The pyrimidine derivative shows an excellent CDK-inhibiting effect and action.

1 . A pyrimidine derivative, wherein the pyrimidine derivative is selected from a compound represented by Formula (I), or a tautomer, an enantiomer, a diastereomer, a mesomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are each independently selected from fluorine or chlorine; 
         R 3  is selected from hydrogen, fluorine, or hydroxyl; 
         A is selected from methylene or a covalent bond; 
         Q is selected from a carbon atom or a nitrogen atom, wherein 
         in case Q is a carbon atom, X is —NR 4 R 6 ; 
         in case Q is a nitrogen atom and R 3  is hydrogen, X is —R 5 ; 
         in case Q is a nitrogen atom and R 3  is fluorine or hydroxyl, X is C 1 -C 3  alkyl, C 3 -C 7  cycloalkyl, or R 5 ; 
         R 4  is selected from hydrogen or C 1 -C 3  alkyl; 
         R 5  is 
       
       
         
           
           
               
               
           
         
       
       in which R, R′, and R″ are each independently selected from hydrogen or C 1 -C 3  alkyl;
 R 6  is C 1 -C 3  alkyl, C 3 -C 7  cycloalkyl, or R 5 . 
 
     
     
         2 . The pyrimidine derivative according to  claim 1 , wherein
 in the compound represented by Formula (I),   when Q is a nitrogen atom and R 3  is hydrogen, R, R′, and R″ in R 5  are each independently selected from hydrogen or methyl;   or, when Q is a nitrogen atom and R 3  is fluorine or hydroxyl, X is ethyl or R 5 , and R, R′, and R″ in R 5  are each independently selected from hydrogen or methyl;   or, when Q is a carbon atom, R 4  is hydrogen or methyl, R 6  is methyl, ethyl, or R 5 , and R, R′, and R″ in R 5  are each independently selected from hydrogen or methyl.   
     
     
         3 . The pyrimidine derivative according to  claim 1 , wherein
 in the compound represented by Formula (I),   both R 1  and R 2  are fluorine, R 3  is hydrogen, A is selected from methylene or a covalent bond, Q is a nitrogen atom, and R, R′, and R″ in R 5  are each independently selected from hydrogen or methyl;   or, both R 1  and R 2  are fluorine, R 3  is fluorine, A is selected from methylene or a covalent bond, Q is a nitrogen atom, and X is ethyl;   or, both R 1  and R 2  are fluorine, R 3  is hydrogen or fluorine, A is selected from methylene or a covalent bond, Q is a carbon atom, R 4  is hydrogen or methyl, and R 6  is methyl, ethyl, or hydroxyethyl.   
     
     
         4 . The pyrimidine derivative according to  claim 1 , wherein the compound represented by Formula (I) is selected from the compounds with the following structures: 
       
         
           
                 
                 
                 
               
                     
                 
                   Compound  
                   Compound  
                   Compound  
                 
                   No. 
                   ID 
                   structure 
                 
                     
                 
                    1 
                   1963 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    2 
                   1964 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    3 
                   1967 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    4 
                   1975 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    5 
                   1978 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    6 
                   1979 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    7 
                   1983 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    8 
                   1984 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                    9 
                   1985 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   10 
                   1986 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   11 
                   1987 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   12 
                   1988 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   13 
                   1990 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   14 
                   1994 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   15 
                   1995 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   16 
                   1999 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . A method for preparing the pyrimidine derivative according to  claim 1 , wherein the method is selected from any one or more of the following methods:
 (1) known compounds I-A and I-B are cyclized to form benzimidazole I-C, I-C is converted to pinacol borate, which then undergoes Suzuki coupling reaction with I-D to form I-E, and I-E finally undergoes Buchwald coupling reaction with the corresponding 2-aminopyridine to form the structure of Formula (I);   
       
         
           
           
               
               
           
         
         (2) 
       
       
         
           
           
               
               
           
         
         (3) 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, R 1 , R 2 , R 3 , A, Q, and X have the same meanings as the corresponding groups in the pyrimidine derivative according to one of  claims 1 - 4 ; Y is halogen. 
       
     
     
         6 . A method for treating abnormal cell proliferative diseases, infections (e.g., viral infections such as herpes, HIV, fungal infection), inflammatory diseases (such as rheumatoid arthritis, osteoarthritis), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), or hematopoietic toxic diseases caused by radiation (such as myelosuppression, neutropenia, leukopenia, anemia) in a subject, comprising a step of administrating a therapeutically effective amount of the pyrimidine derivative according to  claim 1  to the subject. 
     
     
         7 . The method according to  claim 6 , wherein the treatment of abnormal cell proliferative diseases is the treatment of cancer; optionally, the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (such as glioma with malignant astrocytes and oligodendroglioma components), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (such as colon cancer, rectal cancer), lung cancer (such as non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cancer), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (such as cervical cancer, endometrial cancer), head and neck tumor (such as maxillary bone cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer), multiple myeloma, malignant lymphoma (such as reticular cell sarcoma, lymphosarcoma, Hodgkin's lymphoma, mantle cell lymphoma), polycythemia vera, leukemia (such as acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, choriocarcinoma or pediatric tumor (such as Ewing sarcoma, Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma); further optionally, the cancer is breast cancer or ovarian cancer; and more further optionally, the cancer is triple negative breast cancer. 
     
     
         8 . A pharmaceutical composition, comprising the pyrimidine derivative according to  claim 1  as an active ingredient and one or more pharmaceutically acceptable carriers, diluents, or excipients;
 optionally, the pharmaceutical composition further comprises one or more other anticancer agents as active ingredients, which are selected from the group consisting of alkylating agents (such as cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol), platinum complexing agents (such as cisplatin, carboplatin, oxaliplatin), metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed), plant alkaloids (such as vincristine, vinblastine, vindesin, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan), antibody drugs (such as trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab), hormonal anticancer agents (such as leuprorelin, goserelin, dutasteride, dexamethasone, tamoxifen), proteasome inhibitors (such as bortezomib, lenalidomide), aromatase inhibitors (such as exemestane, letrozole, anastrozole), VEGFR or EGFR inhibitors (such as sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib), mTOR inhibitors (such as everolimus, sirolimus, zotarolimus), PI3K kinase inhibitors (such as BKM-120, XL-147, BEZ-235), B-Raf inhibitors (such as vemurafenib, GSK-2118436) or AKT inhibitors (such as perifosine, MK-2206), and the like; one or more other anticancer agents are preferably aromatase inhibitors, more preferably letrozole or anastrozole. 
 
     
     
         9 - 13 . (canceled)